It is now well established that genetic factors play a significant role in antisocial drug dependence. Therefore, knowledge of the action of genes can lead to an understanding of the causes of drug dependence and antisocial behavior. In this component we propose to develop methods that will expedite the discovery of genes involved in this complex human trait. Previous work in the Center has identified a suggestive quantitative trait locus (QTL) on human chromosome 9q, near the telomere, for the multidrug-dependent phenotype. An additional QTL was identified on chromosomes 3q. Based on modeling experiments, the likely region for the location of genes corresponding to the QTL on chromosome 9 is on the order of 20 cM. The major thrust of this proposal, is to develop strategies to locate the genes identified by this QTL with the expectation that they may be generalized to the refinement of other QTLs as well. In association studies, the overall strategy is to define DNA sequences that can be shown to be present more frequently in individuals expressing the trait than in individuals that do not. An advantage of this approach over more traditional genetic linkage approaches is that it assumes nothing about the model of inheritance of the trait (non-parametric) and it is readily adapted to studying traits with a continuous phenotypic distribution. In this proposal we describe three aims. In the first aim, we will use combined linkage and association analyses to test genes in the region of the suggestive 9q QTL. This method gains power from limiting the search to a narrow region where genetic linkage has been established. 200 SNP markers will be scored for association with the disorder. In the second aim association with candidate genes will be used to test for statistical association between polymorphisms in genes with known biochemical involvement in behavior and the phenotype. We will use case-control studies, combined linkage and association studies, and transmission disequilibrium techniques. In the third aim we will attempt to establish a DNA pooling strategy that may be used to expedite these association studies in future studies.